The acute and chronic actions of cocaine and amphetamine are thought to be mediated, in large measure, through augmentation of dopamine neurotransmission in forebrain terminal fields. Research in The laboratory of Molecular and Cellular Neuroscience has emphasized athe study of the molecular mechanisms of dopamine action and has identified a protein kinase/protein phosphatase cascade as one of the major intracellular pathways for dopamine neurotransmission. This project proposes to analyze the role of this cascade in the acute and chronic actions of cocaine and amphetamine. The proposed experiments utilize mouse strains lacking particular components of the postsynaptic dopamine signaling pathway; the genes coding for the phosphatase inhibitors, DARPP-32 and inhibitor-1. These mice represent the only animal models lacking a known intracellular target for dopamine action and provide a unique resource with which to study the role of altered dopaminergic signaling in the a c ute and chronic effects of drugs of abuse. The proposed studies will examine the role of DARPP-32 and inhibitor-1 in mediating or modulating (a) the effects of cocaine and amphetamine on the phosphorylation of known dopamine-regulated intracellular targets. (b) the psychomotor stimulant and reward properties of cocaine and amphetamine and (c) the neurotoxic actions of substituted amphetamines. The overall goal of this project is to gain further insight into the neurochemical mechanisms that play critical roles in human substance abuse.